Letter pubs.acs.org/OrgLett
A New Multicomponent Multicatalyst Reaction (MC)2R: Chemoselective Cycloaddition and Latent Catalyst Activation for the Synthesis of Fully Substituted 1,2,3-Triazoles Kosuke Yamamoto, Theodora Bruun, Jung Yun Kim, Lei Zhang, and Mark Lautens* Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, Canada M5S 3H6 S Supporting Information *
ABSTRACT: A multicomponent multicatalyst reaction (MC)2R for constructing fully substituted 1,2,3-triazoles is reported. An application of chemoselectivity and latent catalysis in a sequence of multicatalytic reactions confers control over a number of undesired processes, where all of the reagents coexist in the same reaction vessel. The sequence of a chemoselective coppercatalyzed azide alkyne cycloaddition followed by a palladium/copper-catalyzed Sonogashira cross-coupling afforded 1,2,3triazoles regioselectively with good to high yields and a broad scope.
W
Scheme 1. Chemoselectivity and Latent Catalyst Activation Enabled (MC)2R
hen a number of substrates are placed in a single reaction vessel containing several catalysts, the selective and orderly assembly of these components is challenging but necessary if a single product is to emerge. The role of metal catalysts is to ensure that desired reactions occur in a specific order so as to minimize “off-path” or “parasitic” processes. As a result, significant a research effort has been invested in the development of switchable or latent catalysis based on heat,1 light,2 or mechanical3 stimuli to gain temporal control. In seeking to achieve subtle catalyst control in more complex reaction sequences, we have studied the use of multiple catalysts that confer chemoselectivity and latent activation in multicomponent reactions,4 where closely related reactants coexist with a number of possible interfering processes (Scheme 1). We now report a copper-catalyzed cycloaddition of an organic azide with two closely related alkyne species with differential rates of reactivity affording remarkable chemoselectivity. The resulting cycloadduct, an iodotriazole, is stable under the reaction conditions at room temperature. Upon heating the reaction mixture, the latent Pd catalyst is activated, promoting a Pd/Cu cocatalyzed Sonogashira reaction to provide a fully substituted triazole. We demonstrate the importance of the choice of catalysts in providing the chemoselectivity and latent activation that led to temporal control and the minimization of interfering processes in the reaction pathway. © XXXX American Chemical Society
Based on our strategy, we accessed two modes of copper catalysis in the direct synthesis of fully substituted 1,2,3triazoles. These important motifs are used in a wide range of applications, including medicinal chemistry, crop science, materials, and bioconjugation.5 Preexisting methods that accessed these fully substituted triazoles were limited by selectivity and scope. For example, Fokin and co-workers6 reported a regioselective ruthenium-catalyzed azide alkyne cycloaddition (RuAAC) of internal alkynes that contained directing groups or an electronic bias. Other approaches include one-pot copper-catalyzed azide alkyne cycloaddition Received: April 14, 2016
A
DOI: 10.1021/acs.orglett.6b00975 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
diyne 7 and 8 would reduce the maximum possible yield of the final product even if diynes do not undergo the CuAAC. Finally, we found the use of palladacycle precatalyst developed by the Buchwald group was important in restoring reactivity for the formation of iodotriazole 4a (entry 9). XPhos-Pd-G3 releases the active monoligated Pd0 catalysts in the presence of base.13 Catalyst activation could occur with carbonate bases as low as room temperature. However, with a weaker base such as KOAc, the precatalyst remained inactive.14 When subjecting the iodoalkyne to the XPhosPd-G3 in the presence of KOAc and excess phenyl acetylene, we did not observe any diyne cross-coupling product (eq 1).
(CuAAC) of terminal alkynes followed by copper-catalyzed C−H arylation7 or CuAAC followed by an oxidative alkynylation, incorporating 2 equiv of an alkyne.8 Recently, Xu and co-workers reported the one-pot synthesis of 5-aryl1,2,3-triazoles using a stoichiometric Cu and Pd catalyst by transmetalation between a copper-triazolide and a Pd-aryl species.9 Conversely, the (MC)2R provided a divergent and regioselective synthesis with alkyne differentiation, affording products with good to high yields. The recent study of the CuAAC indicated that the CuAAC with iodoalkynes may proceed via a different activation pathway from that with terminal alkynes.10 Furthermore, the reactivity of iodoalkynes toward CuAAC exceeds that of terminal alkynes.10a We observed a chemoselective coppercatalyzed formation of 5-iodotriazole 4a from benzyl azide 1a and a mixture of iodoalkyne 2a in the presence of phenyl acetylene 3a in an equimolar ratio in THF (Table 1, entry 1).
However, by using a Pd(OAc)2/XPhos system instead of the precatalyst, a decomposition of iodoalkyne was observed. The inactive precatalyst prevented possible interference of the chemoselective CuAAC and further enforced the desired reaction pathway. Concurrently, we sought conditions for the Cu/Pdcatalyzed Sonogashira cross-coupling of iodotriazole 4a with phenyl acetylene. While a number of conditions have been reported,15 we also observed this transformation was possible using the palladium catalyst XPhos-Pd-G3 at 85 °C (eq 2).16
Table 1. Competition Studies of the CuAAC for Iodoalkynes in the Presence of Terminal Alkynes and Pda
entry
solvent
[Pd]/L
base
yieldb (%) (4a:5:6:7:8)
1 2 3 4 5 6 7 8 9
THF dioxane toluene THF THF THF THF THF THF
− − − − − Pd(OAc)2 Pd2dba3 Pd(OAc)2/XPhos XPhos-Pd-G3
− − − Et3N KOAc KOAc KOAc KOAc KOAc
91:0:9:3:0 80:0:16:0:0 36:0:0:32:n.d.c 76:0:23:1:1 81:0:8:0:
